JPH072785A - N-acyltetrahydroisoquinoline as inhibitor against acyl coenzyme a: cholesterol acyl transferase - Google Patents

Abstract

PURPOSE: To obtain a new compound useful in the treatment or prevention of atherosclerosis by inhibiting the esterification and intestinal absorption of cholesterol.

CONSTITUTION: The compound of formula I [R¹ is 10-25C alkyl chain or the like, R² is hydroxy, lower alkyl, lower alkoxy, halogeno, amino or the like; R³ to R⁵ are each H, -(CH₂)_n-Ar (Ar is phenyl, heteroaryl or the like; n is 0 to 2); m is 0 to 2], e.g. N-(6,7-dimethoxy-l-phenyl-1,2,3,4-tetrahydroisoquinoline)-9- Z-octadeceneamide. The compound of formula I is obtained by reacting an amine of formula II with an acid chloride of formula R¹COCl in the presence of a tertiary amine base (e.g. trietylamine) in a solvent (e.g. dichloromethane).

COPYRIGHT: (C)1995,JPO

Description

Detailed Description of the Invention

[0001]

The present invention relates to N-acyl-1,2,
The present invention relates to 3,4-tetrahydroisoquinolines, and pharmaceutical compositions containing these compounds, which are useful for treating and preventing atherosclerosis.

[0002]

BACKGROUND OF THE INVENTION Atherosclerotic coronary heart disease is a major cause of death and coronary morbidity in Western Europe. Risk factors for atherosclerotic heart disease include hypertension, diabetes mellitus, family history, men, smoking and serum cholesterol.
Total cholesterol levels above 225-250 mg / dl are associated with a significant increase in risk.

Cholesterol esters are a major component of atherosclerotic lesions and are the predominant storage form of cholesterol in arterial wall cells. Cholesterol ester formation is also an important step in the intestinal absorption of dietary cholesterol. Intracellular esterification of cholesterol is catalyzed by the enzyme acyl CoA: cholesterol acyltransferase A (ACAT, EC 2.3.1.26). Therefore, inhibition of ACAT appears to inhibit the progression of atherosclerotic lesions, reduce cholesterol ester accumulation in the arterial wall, and block intestinal absorption of dietary cholesterol.

A large number of N-acyl-1,2,3,4-tetrahydroisoquinoline type enzyme inhibitors are known.
US Pat. No. 4,743,450, US Pat. No. 4,63
4,715, U.S. Pat. No. 4,555,503 and European Patent Application Publication 259,838 disclose N-acyl-1,2, an angiotensin I converting enzyme (ACE) inhibitor. 3,4-Tetrahydroisoquinoline-3-carboxylic acid is shown.

US Pat. No. 4,460,775 discloses an ACE inhibitor, N-acyl-1,2,3,4-.
A tetrahydroisoquinoline-1-carboxylic acid derivative is shown.

German Patent Application No. 3,324,744 discloses the ACE inhibitor N-acyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. There is.

US Pat. No. 4,729,985 discloses renin inhibitors of the formula N-acyl-1,2,
3,4-Tetrahydroisoquinoline is shown: Wherein R is H or methyl; R ¹ is phenyl, 1
-Naphthyl, 4-hydroxyphenyl, propyl, isopropyl, 4-imidazolyl and 4-methoxyphenyl; R ² is H, lower alkyl, lower alkoxy,
Phenyl or R ³ -substituted phenyl, where R ³ is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, fluoro or chloro.

[0008] Furthermore, Stenlake
Chem. Abstracts 82 (9): 579.
76v contains N-acyl-1,2,3,4 of the following structural formula
-Tetrahydroisoquinoline is indicated.

[0009]

[0010]

The novel compounds of the present invention are those represented by formula I: (Wherein R ¹ is a carbon chain having 10 to 25 carbon atoms, branched or straight chain, saturated or an alkyl chain containing one or more double bonds; a group consisting of di- (lower alkyl) amino and Ar. An alkyl chain as defined above, which is substituted by one or more substituents selected from the group; -O-, -S
_{O p -, - NH -,} - C (O) -, phenylene, R ² - substituted phenylene, heteroarylene and R ² - 1 one group selected from the group consisting of substituted heteroarylene or 2
Alkyl chains as defined above, interrupted by more than one (where p = 0, 1 or 2 with the proviso that the alkyl chain is 1
One or more than one -NH- group, said -NH- group does not form an amide group with the -C (O)-group); one or more di-
Substituted by (lower alkyl) amino or Ar group, interrupted alkyl chain defined above; diphenylamino; di - (R ² - substituted phenyl) amino; di - (heteroaryl) amino; di - (R ² - substituted heteroaryl) amino; diphenylmethyl; or di - (R ² -
R ² is independently of each other hydroxy, lower alkyl, lower alkoxy, halogeno,
Selected from the group consisting of amino, lower alkylamino and di- (lower alkyl) amino; R ³ , R ⁴ and R ⁵
H or is independently of one another - (CH ₂₎ be _n -Ar;
Ar is selected from the group consisting of phenyl, R ² -substituted phenyl, heteroaryl and R ² -substituted heteroaryl; n = 0, 1 or 2; m = 0, 1 or 2) or agents thereof. It is a physiologically acceptable salt.

Preferred is when R ¹ is CH ₃ (CH ₂ ) ₇ C
_{H = CH (CH 2) 7} - ( i.e. -C (O) -R ¹ is oleoyl) is a compound of formula I is diphenyl acetyl, or diphenylamino.

Also preferred are R ³ , R ⁴ or R.
⁵ is independently H or together - (CH _{2) n} -Ar (wherein, Ar is phenyl or R ² - substituted phenyl)
Is a compound of formula I

Another preferred group of compounds is one of R ³ , R ⁴ or R ⁵ is-(CH ₂ ) _n --Ar, wherein Ar is phenyl or R ² -substituted phenyl, and Is H.

More preferably, R ⁵ is H or phenyl and R ¹ is CH ₃ (CH ₂ ) ₇ CH═CH (C
H _{2) 7} - (i.e. -C (O) -R ¹ is oleoyl) is a compound of formula I is a diphenylmethyl or diphenylamino.

[0015] than another preferred group of compounds, R ⁴ is H, phenyl or di - a (lower alkoxy) phenyl, R ¹ is _{CH 3 (CH 2) 7 CH} = CH (CH 2) 7 -
(I.e., -C (O) -R < ¹ > is oleoyl), diphenylmethyl or diphenylamino.

Yet another more preferred group of compounds is that R ³ is H, 2- (4-chlorophenyl) ethyl,
3,4-dimethoxyphenylmethyl, benzyl or 2
- methylamino-5-chloro - selected from the group consisting of phenyl, R ¹ is _{CH 3 (CH 2) 7 CH} = CH (CH 2) 7 -
(I.e., -C (O) -R < ¹ > is oleoyl), diphenylmethyl or diphenylamino.

Highly preferred is R ⁵ is H or phenyl, R ⁴ is H, phenyl or di- (lower alkoxy) phenyl and R ³ is H, 2- (4-chlorophenyl) ethyl, 3, Selected from the group consisting of 4-dimethoxyphenylmethyl, benzyl or 2-methylamino-5-chloro-phenyl, wherein R ¹ is CH ₃ (CH ₂ ) ₇ C
_{H = CH (CH 2) 7} - ( i.e. -C (O) -R ¹ is oleoyl a is) is a compound of formula I.

The invention likewise relates to a pharmaceutical composition comprising an ACAT inhibitor of formula I in a pharmaceutically acceptable carrier.

In yet another aspect, the invention provides compounds of formula I
Compound of a: (In the formula, R ^1a represents ¹ to 25 carbon atoms, branched or straight chain, saturated or an alkyl chain containing 1 or 2 or more double bonds; one substituent selected from the group consisting of U or substituted by 2 or more, the alkyl chain defined _{above; -O -, - SO p -} , - NH -, - C (O) -, phenylene, R ² - substituted phenylene, heteroarylene and R ² - substituted heteroaryl An alkyl chain as defined above interrupted by one or more groups selected from the group consisting of arylene (where p = 0, 1 or 2);
R ² is an interrupted alkyl chain as defined above, which is substituted by one or more substituents selected from the group consisting of U; R ² is independently of each other hydroxy, lower alkyl, lower alkoxy, halogeno, amino, lower selected from (lower alkyl) group consisting of amino - alkylamino and di; R ^3, R ⁴ and R ⁵ are independently H or together - (CH ₂₎ be _n -Ar; Ar is phenyl, R ² -
Selected from the group consisting of substituted phenyl, heteroaryl and R ² -substituted heteroaryl; U is di- (lower alkyl) amino, diphenylamino, di- (R ² -substituted phenyl) amino, diheteroarylamino, di- (R ² -
A substituted heteroaryl) amino and Ar; n = 0, 1 or 2, m = 0, 1 or 2) or a pharmaceutically acceptable salt thereof as an ACAT inhibitor. It is about using.

The compounds of formula Ia are preferably administered in a pharmaceutically acceptable carrier and are used as blood lipid lowering agents and blood cholesterol lowering agents in mammals.

As used herein, "lower alkyl" means a straight or branched alkyl chain of 1-6 carbon atoms and "lower alkoxy" similarly represents an alkoxy group of 1-6 carbon atoms.

Halogeno represents a fluorine, chlorine, bromine or iodine radical.

"Phenylene" means a divalent phenyl group, including ortho, meta and para substitution, "heteroarylene" also means a divalent heteroaryl group.

Heteroaryl means an aromatic residue containing 5-6 ring members, of which 1-3 ring members independently of one another are selected from the group consisting of nitrogen, oxygen and sulfur. To do. Examples of heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl and thianyl.

When the tetrahydroisoquinolyl moiety is substituted by more than one R ² group (ie m =
2), these R ² groups may be the same or different and may be located in the 5, 6, 7 or 8 position of the ring system.

The alkyl chain defined in R ¹ and R ^1a may be the residue of a synthetic or natural fatty acid, which is saturated or which has one or more carbon-carbon double bonds. Containing or containing 1 or 2 or more carbon atoms in the chain —O—, —S—, —SO—, —SO ₂
-, - C (O) - , - NH-, phenylene, R ² - substituted phenylene, heteroarylene or R ² - may be interrupted alkyl chain was replaced with a substituent heteroarylene group. When substituted by a disubstituted amino, or an optionally substituted phenyl or heteroaryl group, the alkyl or interrupted alkyl chains are independently substituted at different carbon atoms or at one carbon atom. It may be di-substituted or both.

When the interrupted alkyl chain defined in R ¹ and R ^1a contains one or more groups --NH--, these --NH-- groups are directly bonded to the --C (O)-group. They cannot together form an amide group. When two or more interrupting -NH- groups are present, even if these two -NH- groups are directly bonded to the same -C (O)-group and they together form a urea group. Good.

The double bonds present, the exchange of carbon atoms in the chain, and the number of substituents present on the carbon atoms in the chain all depend on the length of the chain; shorter alkyl chains are more numerous than longer alkyl chains. It will be apparent to those skilled in the art that it cannot contain any bonds, carbon exchanges or substituents. Unsaturated alkyl chains generally contain 1-4 conjugated or non-conjugated double bonds.
If carbon atoms are exchanged, there may generally be 1-4 exchange groups present. Similarly, if carbon atoms are substituted, then 1-4 substituents may be present.

Examples of alkyl chains are the following, in which the group --C (O)-R ¹ is mentioned: palmitoyl, stearoyl and 2,2-dimethyldodecanoyl.

Examples of unsaturated --C (O)-R ¹ groups are oleoyl, linoleoyl, linolenoyl, elideyl,
Eicosatetraenoyl, eicosapentaenoyl and arachidonoyl.

Carbon atoms in the chain have been exchanged --C
Examples of (O) -R ¹ groups are 3-methoxy-4- (tetradecyloxy) benzoyl, 11- [N- (2,2-diphenylacetyl) amino] undecanoyl and phenoxyundecanoyl.

An example of a disubstituted amino-C (O) -R ¹ group is N, N-diphenylaminocarbonyl.

The compounds of formula I ^a in terms encompasses compounds other groups defined by the form of compounds all, and a group R ^1a in the compound of Formula I, Formula I is a subclass of compounds of formula I ^a . The definition of the group R ^1a includes, in addition to the C ₁₀ -C ₂₅ chain defined by R ¹ , C ₁ -C ₉ alkyl chains, substituted alkyl chains, interrupted alkyl chains, and substituted and interrupted Alkyl chains are included.

The compounds of this invention contain one or more asymmetric carbon atoms and may therefore include rotamers. The present invention includes all possible stereoisomers both in pure form and in mixed form, including racemic mixtures.
Isomers may be prepared by conventional methods, by reacting the enantiomeric starting materials, or by separating the isomers of the compound of formula I.

The isomers may include geometrical isomers, for example when R ¹ contains a double bond. All of these isomers are included in the present invention.

The compounds of the present invention containing an amino group are capable of forming pharmaceutically acceptable salts with organic and inorganic acids. Examples of acids suitable for forming salts are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, which are well known to those skilled in the art.
Ascorbic acid, maleic acid, methanesulfonic acid and other mineral and carboxylic acids. Salts are prepared by contacting the free base form with a sufficient amount of the desired acid to form salts. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydrogen carbonate solution. The free base form differs somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but otherwise salts are different from their respective free base forms for the purposes of the present invention. It is even.

Certain compounds of the present invention are acidic (eg, compounds containing phenolic residues or carboxyl groups). These compounds are capable of forming pharmaceutically acceptable salts with organic and inorganic bases. Examples of these salts are sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine and the like.

Compounds of formula I may be prepared under standard reaction conditions well known in the art. For example, a carboxylic acid of formula II is converted to the acid chloride by treatment with thionyl or oxalyl chloride in a solvent such as dichloromethane, then a tertiary amine base such as triethylamine, 4-dimethylaminopyridine (DMA).
P) or N-methylmorpholine (NMM) can be reacted with an amine of formula III: Alternatively, salts of amines of formula III may be treated similarly to formula I
Compounds of can be prepared.

Another method is to use an acid of formula II and an amine of formula III with a coupling agent such as dicyclohexylcarbodiimide (DCC) or 1- (3'-dimethylaminopropyl) -3-ethylcarbodiimide (EDC).
I), and by reacting in the presence of a base such as triethylamine, dimethylaminopyridine (DMAP) or N-methylmorpholine (NMM) in a solvent such as dichloromethane, tetrahydrofuran or dimethylformamide.

In the fourth method, the carboxyl group of acid II can be activated with an active ester intermediate, such as one derived from 1-hydroxybenzotriazole (HOBT).

Starting acids of formula II are either commercially available or can be prepared by well known methods. Amines of formula III are either commercially available or can be prepared by various methods, some examples of which are given below.

Formula II wherein R ⁴ is -Ar and R ³ is H
In the process for preparing the amine of Ia, the carboxylic acid of formula IV is converted to the acid chloride V with thionyl chloride or oxalyl chloride. Aromatic compound A
Condensation with r-H (VI) gives the ketone of formula VII.
The ketone is reacted with hydroxylamine hydrochloride to form the oxime VIII. About 2.8 of oxime VIII
Hydrogenation in the presence of a suitable catalyst such as 10% palladium on carbon at -3.5 kg / cm ² (40-50 psi) provides amine IX. Reaction of amine IX with formaldehyde in methanol followed by treatment with an acid, for example hydrochloric acid, forms an amine of formula IIIa: Starting acids of formula IV and aryl compounds of formula VI are either commercially available or easily prepared by methods well known to those skilled in the art.

In the process for preparing amines of formula IIIb where R ⁴ is H, an amine of formula XI is condensed with an aldehyde of formula X to give an imine of formula XII. This imine is treated with an acid chloride, such as 2-chloroacetyl chloride, in the presence of aluminum chloride to form the cyclic amide XIII. Hydrolysis of amide XIII with thiourea in ethanol gives the desired amine IIIb: Starting amines of formula XI and aldehydes of formula X are either commercially available or easily prepared by well known methods.

Another method for preparing amines of formula IIIb is by coupling an acid of formula XIV with an amine of formula XI to form amide XV. Treatment of this amide with phosphorus oxychloride produces imine XVI, which is reduced with sodium borohydride to amine IIIb: Starting acids of formula XIV are either commercially available or easily prepared by known methods.

A third method for preparing amines of formula IIIb
Method of reacting an amine of formula XVII with an epoxide of formula XVIII. The amino-alcohol XIX obtained
Is treated with methanesulfonic acid to give the desired amine III: Starting amines XVII and epoxides XVIII are either commercially available or can be readily prepared by methods well known to those skilled in the art.

Reactive groups that do not participate in the above treatment can be protected by a usual protecting group during the reaction, and can be removed by a standard method after the reaction. The table below shows some common protecting groups: Compounds of formula Ia can be prepared by similar methods.

The inventors have found that the compounds of formula I and Ia are in vitro inhibitors of ACAT.
The novel compounds of formula I form a subclass of compounds of formula Ia. The compounds of the invention are therefore blood cholesterol lowering agents and blood lipid lowering agents by virtue of their ability to suppress cholesterol esterification and intestinal absorption; they are therefore atherosclerotic in mammals, especially humans. It is useful for the treatment and prevention of.

Accordingly, the present invention, in addition to the compound aspect, also relates to a method of treating atherosclerosis, particularly by lowering serum cholesterol, which method provides blood to a mammal in need of such treatment. It comprises administering a cholesterol-lowering effective amount of a compound of formula I or Ia or a pharmaceutically acceptable salt thereof. These compounds are preferably administered in a pharmaceutically acceptable carrier suitable for oral administration.

The in vitro activity of the compounds of formula I or Ia can be measured by the following method.

ACAT Assay (In Vitro) This assay uses tritiated oleic acid as ACAT.
ACAT activity is measured by measuring the mediated transfer of acyl-CoA to cholesterol to labeled cholesterol oleate. Rat liver microsomes are used as the source of ACAT. The assay is performed in round bottom microtiter plates with a total incubation volume of 50 μL. 10 μL of assay buffer (0.5M
KHPO ₄ , 10 μM dithiothreitol, pH 7.
4), 7.5 μL of 40 mg / mL BSA (bovine serum albumin) and 12.5 μg of microsomal protein are charged. Test compounds (sufficient to reach a final concentration of 0.1-25 μM), reference compound, or vehicle control are added to make a final volume of 47 μL. The microtiter plate is then floated on the surface of a 37 ° C water bath for 15 minutes. Incubation is initiated by the addition of ³ μL of ³ H-acyl CoA (1 μCi / well, final concentration 10 μM acyl CoA). Then plate 1 in a water bath
Return for 5 minutes. Then 15 μL from each incubation
The incubation is stopped by applying to each row of a thin layer plate (silica gel GF 20 × 20 cm). The reference substances are given in a series so that cholesterol can be identified. After drying the plate, 90: 1
Elute with 0: 1 petroleum ether: diethyl ether: acetic acid. The reference material is visualized with iodine vapor and the area corresponding to cholesterol ester is scraped into a 7 mL scintillation vial. Add 4 mL scintillant to each vial and quantitate radioactivity. Background counts are measured by boiling controls. Total activity is measured by activity in the presence of vehicle. The inhibition rate is calculated by subtracting the background from both the control and the test sample and calculating the test value as a percentage of the control. To determine the IC ₅₀ , the inhibition rate is plotted against the drug amount on a logarithmic scale and the concentration at which 50% inhibition is obtained is determined.

Representative results are as follows: Following are examples of preparation of starting materials and examples for preparing compounds of Formula I.

[0052]

EXAMPLES Production Example 1: 6,7-Dimethoxy-3-phenyl-1,
2,3,4-Tetrahydroisoquinoline Step A: 3.9 g oxalyl chloride, 2.0 g 3,4-dimethoxyphenylacetic acid and 50 mL benzene were admixed and the mixture was stirred at 60 ° C. for 2.5 hours.
Excess oxalyl chloride was distilled off and the solution was concentrated to a volume of 20 mL. The solution is cooled to room temperature and benzene 300 is added.
A suspension of anhydrous aluminum chloride (1.6 g) in mL was added slowly over 12 hours. The reaction mixture was stirred for 6 hours, poured into a mixture of ice and concentrated hydrochloric acid and then extracted with ethyl acetate. The organic extract was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to give a residue. The residue was chromatographed on silica gel with 3: 7 ethyl acetate / hexane to give 847 mg of α- (3,4-dimethoxyphenyl) -acetophenone. ¹ H NMR
_{(CDCl 3): δ 8.1-7.98 (} 2H, m);
7.62-7.4 (3H, m); 6.76-6.9 (3
H, m); 4.24 (2H, s); 3.85 (6H,
s).

Step B: 250 mg of hydroxylamine hydrochloride was added to a solution of the ketone from Step A in 10 mL of pyridine at 0 ° C. and stirred for 3.5 hours. The reaction mixture was poured into water and extracted with diethyl ether. The ether extract was washed with water and 1N HCl (aq) then dried over Na ₂ SO ₄ . It was filtered and the filtrate was concentrated to give a residue. The residue was chromatographed (silica gel, 1: 1 ethyl acetate / hexane) to give 853 mg of the desired oxime. ¹ H NMR (CDCl ₃ ):
δ 7.67-7.55 (2H, m); 7.4-7.2
7 (3H, m); 6.86-6.64 (3H, m);
4.16 (2H, s); 3.8 (3H, s); 3.78
(3H, s).

Step C: The oxime from Step B was dissolved in a solution of 1M HCl in ethanol (20 mL) and about 3.4 kg / cm ² (48 psi) on 10% palladium on carbon (25 mg) for 3 hours. Hydrogenated.
The mixture was filtered, the filtrate was neutralized with NaHCO ₃ (aq) and extracted with ethyl acetate. Concentrate the organic extract to 2
Obtained 75 mg of 1-phenyl-2- (3,4-dimethoxyphenyl) ethyl-amine. ¹ H NMR (CDC
_{l 3): δ 7.42-7.2 (5H} , m); 6.84
-6.68 (2H, m); 6.57 (1H, d, J = 2
Hz); 4.17 (1H, dd, J = 9 and 5H
z); 3.86 (3H, s); 3.78 (3H, s);
2.97 (1H, dd, J = 14 and 5 Hz);
78 (1H, dd, J = 14 and 9Hz); 1.57
(2H, br.s).

Step D: A mixture of amine from Step C, 36% formaldehyde (1 mL) and 1.5 mL of methanol was heated to reflux for 2 hours. The solvent was evaporated, 3 mL of benzene was added to the residue and concentrated in vacuo to give a residue. 3 mL of benzene was added and concentrated again to give a residue. 2 mL of methanolic HCl (1.5N) was added and the mixture was heated to reflux for 2 hours. The mixture was poured into water, neutralized with NH ₄ OH, and extracted with ethyl acetate. The extract was concentrated to give 286 mg of the title compound. ¹ H
_{NMR (CDCl 3): δ 7.53-7.23} (5
H, m); 6.6 (2H, d, J = 2Hz); 4.3-
3.72 (3H, m); 3.87 (3H, s); 3.8
5 (3H, s); 2.9 (2H, d, J = 7Hz).

In a similar manner, 3- (3,4-dimethoxy-phenyl) -6,7-dimethoxy-1,2,3,4
-Tetrahydroisoquinoline may be prepared.

Production Example 2: 6,7-dimethoxy-1-fu
Phenyl- 1,2,3,4-tetrahydroisoquinoline Step A: 2- (3,4-dimethoxyphenyl) ethylamine (1 g) and benzaldehyde (585 mg)
In toluene (25 mL) was heated to reflux for 3 hours. The solvent was distilled off to obtain N- [2- (3,4-dimethoxyphenyl) ethyl] benzylimine (1.5 g).
¹ H NMR (CDCl ₃ ): δ 8.14 (1H,
s); 7.74-7.66 (2H, m); 7.46-
7.36 (3H, m); 6.82-6.72 (3H,
m); 3.85 (3H, s); 3.84 (2H, t, J
= 7 Hz); 3.79 (3H, s); 2.98 (2H,
t, J = 7 Hz).

Step B: 200 mg of imine from step A
Was dissolved in 1,2-dichloroethane (8 mL) to obtain 84 m
g 2-chloroacetyl chloride was added and the mixture was adjusted to 1
Stir for 5 minutes. 100 mg of aluminum chloride (anhydrous) was added and stirred for 3 hours. The reaction mixture is concentrated HCl
And poured into ice and then extracted with chloroform. Chloroform extract was added sequentially to water and NaHCO ₃ (aqueous solution)
And washed with brine, then concentrated to 200 mg
N- (2-chloroacetyl) -6,7-dimethoxy-
1-Phenyl-1,2,3,4-tetrahydroisoquinoline was obtained.

Step C: Thiourea (45 mg), Step B
A mixture of the product of Example 1 and ethanol (8 mL) was heated to reflux for 3 hours. The solvent was removed in vacuo, the residue was dissolved in chloroform and filtered. The filtrate is concentrated to 153
Obtained mg of the title compound. ¹ HNMR (CDCl ₃ ): δ
7.4-7.18 (5H, m); 6.63 (1H,
s); 6.24 (1H, s); 5.03 (1H, s);
3.85 (3H, s); 3.61 (3H, s); 3.2
8-2.65 (4H, m); 2.3 (1H, br.
s).

Production Example 3: 1- [2- (4-chlorophene
Nyl) ethyl] -6-methyl-7-methoxy-1,2,
3,4-Tetrahydroisoquinoline Step A: 2- (3-Methyl-4-methoxyphenyl)
Ethylamine (64.4 g) and 3- (4-chlorophenyl) -propionic acid (70.2 g) in xylene (6
The solution in (00 mL) was heated to reflux with a Dean-Stark trap for 5.5 hours. The hot reaction mixture was poured into water and left overnight. The solid was collected by filtration and recrystallized from ethanol to give N- [2- (3-methyl-4-methoxyphenyl) ethyl] -3- (4-chlorophenyl) propionamide (101.1 g). Melting point = 142-
144 ° C.

Step B: Amide from Step A (10.0
g), phosphorus pentoxide (25 g), phosphorus oxychloride (15 m
L) and xylene (250 mL) for 2 hours,
Heated to reflux. Cool the reaction mixture, water (500 mL)
Was gradually added, made basic with NaOH, and extracted with benzene. The benzene extract was concentrated to a residue and triturated with diethyl ether to give 6-methyl-7-methoxy-1- [2- (4-chlorophenyl) ethyl] -3,
4-Dihydroisoquinoline (4.95 g) was obtained. Melting point = 122-124 [deg.] C.

Step C: Sodium borohydride (2.
0 g) was added to a suspension of dihydroisoquinoline (4.75 g) from step B in ethanol (175 mL) and the mixture was stirred for 2 hours. The residue was concentrated, treated with water and heated on a steam bath for 0.75 hours. The mixture was cooled to room temperature, extracted with ether and the ether extract was concentrated to a residue. The residue was dissolved in ethyl acetate and 1.7 g
And the resulting salt was recrystallized from ethanol / ethyl acetate to give the title compound as a maleate salt (4.05 g). Elemental analysis: C ₁₉ H ₂₂ ClNO ₂
Calculated value C = 63.9%, H = 6.03%, N =
3.25%; Found, C = 63.91, H = 5.99,
N = 3.22.

By the same method, 1-benzyl-6,7-
Dimethoxy-1,2,3,4-tetrahydroisoquinoline can be prepared.

Production Example 4: 6,7-Dimethoxy-4-f
Phenyl-1,2,3,4-tetrahydroisoquinoline Step A: 3,4-dimethoxybenzyl-amine (1
A solution of 6.7 g) and styrene oxide (12.0 g) in acetonitrile (250 mL) was heated to reflux for 16 hours. Concentrate the residue and distill the residue to 120 ° C.
The fraction distilled over (0.5 mm) or more was collected. The solidified distillate was recrystallized from benzene / hexane to give N-
(3,4-dimethoxybenzyl) -2-hydroxy-2
-Phenylethyl-amine (13.4 g) was obtained. Melting point = 93-94 ° C.

Step B: The amino alcohol from Step A (2.2 g) was added to a mixture of methanesulfonic acid (100 mL) and dichloromethane (150 mL) and stirred at room temperature overnight. The mixture was poured into ice water and the organic layer was concentrated to give a residue. Trituration with benzene followed by recrystallisation from ethanol gave 8.7 g of the title amine as the methanesulfonate salt. Melting point = 198-199 [deg.] C.

Production Example 5: 1-benzyl-6,7-dihi
Droxy-1,2,3,4-tetrahydroisoquinoline 1-benzyl-6,7-dimethoxy-1,2,3,4-
Tetrahydroisoquinoline (10 g) with 48% HBr
(100 mL) and the mixture was heated to reflux under nitrogen for 2 hours. The mixture was cooled to room temperature and crystals were formed overnight. The crystals were collected and washed with cold ethanol to give 7.5 g of the title compound as its HBr salt. Melting point = 23
3-236 ° C.

Example 1: N- (6,7-dimethoxy-
1-phenyl-1,2,3,4-tetrahydroisoquino
Phosphorus) -9-Z- octadecenamide 188 mg of oleyl chloride was combined with 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (153 mg) and triethylamine (76 m).
g) to a solution in dichloromethane (5 mL), 2
Stir for hours. The mixture was poured into water, extracted with dichloromethane, and the extract was concentrated to give a residue. The residue was chromatographed (silica gel, 5:95 ethyl acetate / dichloromethane) to give the title compound (230 mg). ms (FAB) = 534 (M ⁺ 1).

The following compounds were prepared by a similar method: Example 2: N- (6,7-dimethoxy-4-phenyl
-1,2,3,4-Tetrahydroisoquinoline) -9-
Z-octadecenamide 350 mg oleyl chloride was dissolved in a solution of 6,7-dimethoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline methanesulfonate (350 mg) and triethylamine (435 mg) in diethyl ether. And stirred for 2.5 hours. The mixture was diluted with ethyl acetate, filtered and the filtrate concentrated to give a residue. Chromatography on silica gel (4: 6 ethyl acetate / hexane) gave 480 mg of the title compound. ms
= 534 (M ⁺ 1).

Example 3: N- (6,7-dimethoxy-
3-phenyl-1,2,3,4-tetrahydroisoquino
Phosphorus) -9-Z-octadecenamide 6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (286
mg) solution, oleic acid (300 mg), 240 m
g of dicyclohexyl-carbodiimide (DCC), 5
Added to a mixture of mg 4-dimethylaminopyridine (DMAP) and methylene chloride (5 mL) and stirred for 22 hours. The mixture was filtered and concentrated to give a residue. Chromatography on silica gel (3: 7 ethyl acetate / hexane) gave the title compound (346 mg). m
s = 534 (M ⁺ 1).

The following compound was prepared by a similar method: N- [6,7-dimethoxy-3- (3.4-dimethoxyphenyl) -1,2,3,4-tetrahydroisoquinoline] -9-Z- Octadecenamide, ms = 594
(M ⁺ 1); and N- [1- (2-methylamino-5
-Chlorophenyl) -1,2,3,4-tetrahydroisoquinoline] -9-Z-octadecenamide, ms (F
AB) = 537 (M ⁺ 1).

Example 4: N- (1-benzyl-6,7)
-Dihydroxy-1,2,3,4-tetrahydroisoxy
Norrin) -9-Z-octadecenamide 1- (3′-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (410 mg) was added to 1-benzyl-
6,7-Dihydroxy-1,2,3,4-tetrahydroisoquinoline (500 mg), oleic acid (560 m
g), 1-hydroxybenzotriazole (290 m
g), N-methyl-morpholine (220 mg) and dimethylformamide (8 mL) and added 18
Stir for hours. The mixture is poured into water, extracted with ethyl acetate, the combined extracts are dried over Na ₂ SO ₄ , filtered,
The filtrate was concentrated to give a residue. The residue was chromatographed on silica gel (1: 1 ethyl acetate / hexane) to give the title compound (460 mg). ms = 520
(M ⁺ 1).

The following formulations exemplify some of the dosage forms of the present invention. In each case the term "active compound" refers to the formula I
Or a compound of Ia, preferably N- (6,7-dimethoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline) -9-Z-octadecenamide. However, instead of this compound it is likewise possible to use effective amounts of other compounds of the formula I or Ia.

Example A Tablet No. Ingredient mg / tablet mg / tablet 1 Active compound 100 500 2 Lactose USP 122 113 3 Corn starch, food grade, 30 40 No. as a 10% paste in purified water. Ingredient mg / tablet mg / tablet 4 Corn starch, food grade 45 40 5 Magnesium stearate 3 7 Total 300 700 Preparation method Ingredient No. 1-15 in a suitable mixer 10-15
Mix for minutes. The mixture was mixed with ingredient no. Granulate with 3. Wet granules if necessary with a coarse screen (eg 1
/ 4 ", 0.63 cm). Dry the wet granules. If necessary, sift the dry granules, ingredient N
o. Mix with 4 and mix for 10-15 minutes. Ingredient No.
Add 5 and mix for 1-3 minutes. The mixture is pressed on a suitable tabletting machine to the appropriate size and weight.

Example B Capsule No. Ingredient mg / tablet mg / tablet 1 Active compound 100 500 2 Lactose USP 106 123 3 Corn starch, food grade, 40 70 5 Magnesium stearate NF 4 7 Total 250 700 Preparation method Ingredient No. 1, 2 and 3 in a suitable blender 10
Mix for 15 minutes. Ingredient No. Add 4 and mix for 1-3 minutes. Mix the mixture in a suitable encapsulation machine to the appropriate 2
Fill individual hard gelatin capsules.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] July 21, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Claims]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location C07D 217/20 (72) Inventor Timothy Cogan, California, USA 94019, Half Moon Bay, St. John Avenue 412

Claims (16)

[Claims] 1. A compound of the formula: (In the formula, R ¹ is an alkyl chain containing 10 to 25 carbon atoms, branched or straight chain, saturated or 1-4 double bonds; selected from the group consisting of di- (lower alkyl) amino and Ar. substituted by 1-4 substituents, the alkyl chain defined _{above; -O -, - SO p -} , - NH -, -
C (O) -, phenylene, R ² - substituted phenylene, heteroarylene and R ² - is interrupted by 1-4 group selected from the group consisting of substituted heteroarylene, alkyl chain (where p = 0 is provided for in the 1 or 2,
Provided that when the alkyl chain is interrupted by 1-4 -NH- groups, the -NH- group does not form an amide group together with -C (O)-group); -(Lower alkyl) amino or an interrupted alkyl chain as defined above substituted with an Ar group; diphenylamino;
Di - (R ² - substituted phenyl) amino; di - (heteroaryl) amino; di - (R ² - substituted heteroaryl) amino; diphenylmethyl; or di - (R ² - substituted phenyl) are methyl; R ² Is hydroxy independently of each other,
Lower alkyl, lower alkoxy, halogeno, amino, lower alkylamino and di - selected from (lower alkyl) group consisting of amino; R ^3, R ⁴ and R ⁵ are independently H or together - (CH _{2) n} -Ar in it; Ar is phenyl, R ² - substituted phenyl, heteroaryl and R ² - is selected from the group consisting of substituted heteroaryl; be n = 0, 1 or 2; a m = 0, 1 or 2) or Those pharmaceutically acceptable salts. 2. -C (O) -R ¹ is oleoyl, stearoyl, palmitoyl, linoleic oil, linolenoyl, eridoyl, arachidonoyl, aicosapentaenoyl, eicosateraenoyl, diphenylacetyl, 2,2-dimethylundeca. Noyl, 3-methoxy-
The compound according to claim 1, which is selected from the group consisting of 4- (tetradecyloxy) benzoyl, phenoxyundecanoyl and N, N-diphenylaminocarbonyl. 3. A compound according to claim 1 or 2, wherein R ² is hydroxy, methyl or lower alkoxy and m = 0 or 2. 4. One of R ³ , R ⁴ or R ⁵ is — (CH ₂ ).
(wherein, Ar is a phenyl or R ² - substituted phenyl) _n -Ar is, others are H, A compound according to claim 1, 2 or 3. Wherein R ⁴ is H, phenyl or di - (lower alkoxy) phenyl, claims 1, 2, 3 or 4
The compound according to. 6. R ³ is H, 2- (4-chlorophenyl)
A compound according to claim 1, 2 or 3 selected from the group consisting of ethyl, 3,4-dimethoxyphenylmethyl, benzyl or 2-methylamino-5-chloro-phenyl. 7. The compound according to claim 1, 2, 3, 5 or 6, wherein R ⁵ is H or phenyl. 8. The compound according to claim 1, 3, 4, 5, 6, or 7, wherein —C (O) —R ¹ is oleoyl, diphenylacetyl or N, N-diphenylaminocarbonyl. 9. A compound according to claim 1 represented by the formula: here, . 10. ACAT-suppressive effective amount of claim 1.
A pharmaceutical composition for treating atherosclerosis in a mammal, which comprises the compound according to 1. in a pharmaceutically effective carrier. 11. The composition according to claim 10, which is a dosage form.
The pharmaceutical composition according to 1. 12. A process for preparing a pharmaceutical composition, which comprises mixing a compound according to claim 1 with a pharmaceutically acceptable carrier. 13. Use of a compound according to claim 1 in the preparation of a medicament for the treatment of atherosclerosis. 14. A method for producing a compound according to claim 1, which comprises: (a) an amine of the following formula: Alternatively, a salt thereof (wherein R ² , R ³ , R ⁴ , R ⁵ and m are defined in claim 1) and a formula R ¹ COCl
Reacting the acid chloride of formula (wherein R ¹ is as defined in claim 1) in the presence of a tertiary amine base;
Or (b) amine of the following formula Alternatively, a salt thereof (wherein R ² , R ³ , R ⁴ , R ⁵ and m are defined in claim 1) and a formula R ¹ COOH
The carboxylic acid of the formula (wherein R ¹ is as defined in claim 1) is reacted in the presence of a coupling agent and a base in a suitable solvent, the carboxylic acid optionally being 1-
Activated with hydroxybenzotriazole. 15. An ACAT-inhibiting effective amount of a compound of the formula: (In the formula, R ^1a represents an alkyl chain having 1 to 25 carbon atoms, a branched or straight chain, a saturated or a double bond having 1 to 4 carbon atoms;
Substituted by 1-4 substituents selected from the group consisting of U, the alkyl chain defined _{above; -O -, - SO p -} ,
-NH -, - C (O) -, phenylene, R ² - substituted phenylene, heteroarylene and R ² - is interrupted by 1-4 group selected from the group consisting of substituted heteroarylene, alkyl chain defined above ( Where p = 0, 1 or 2); Substituent 1-4 selected from the group consisting of U
An interrupted alkyl chain as defined above, which is substituted by R; R ² independently of one another is of the group consisting of hydroxy, lower alkyl, lower alkoxy, halogeno, amino, lower alkylamino and di- (lower alkyl) amino. selected; R ^3, R ⁴ and R ⁵ are independently H or together - (CH ₂₎ be _n -Ar; Ar is phenyl, R ²
- selected from the group consisting of substituted heteroaryl - substituted phenyl, heteroaryl and R ^2; U is di - (lower alkyl) amino, diphenylamino, di - (R ² - substituted phenyl) amino, diheteroarylamino, di -(R ²
-Substituted heteroaryl) amino and Ar; n = 0, 1 or 2; m = 0, 1 or 2) or a pharmaceutically acceptable salt thereof. A method of treating atherosclerosis, which comprises administering to a mammal in need thereof a pharmaceutical composition comprising a carrier which is acceptable for said treatment. 16. An ACAT-inhibiting effective amount of a compound of the formula: (In the formula, R ^1a represents an alkyl chain having 1 to 25 carbon atoms, a branched or straight chain, a saturated or a double bond having 1 to 4 carbon atoms;
Substituted by 1-4 substituents selected from the group consisting of U, the alkyl chain defined _{above; -O -, - SO p -} ,
-NH -, - C (O) -, phenylene, R ² - substituted phenylene, heteroarylene and R ² - is interrupted by 1-4 group selected from the group consisting of substituted heteroarylene, alkyl chain defined above ( Where p = 0, 1 or 2); Substituent 1-4 selected from the group consisting of U
An interrupted alkyl chain as defined above, which is substituted by R; R ² independently of one another is of the group consisting of hydroxy, lower alkyl, lower alkoxy, halogeno, amino, lower alkylamino and di- (lower alkyl) amino. selected; R ^3, R ⁴ and R ⁵ are independently H or together - (CH ₂₎ be _n -Ar; Ar is phenyl, R ²
- selected from the group consisting of substituted heteroaryl - substituted phenyl, heteroaryl and R ^2; U is di - (lower alkyl) amino, diphenylamino, di - (R ² - substituted phenyl) amino, diheteroarylamino, di -(R ²
-Substituted heteroaryl) amino and Ar; n = 0, 1 or 2; m = 0, 1 or 2) or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for the treatment of atherosclerosis in a mammal comprising in a carrier acceptable to the.